CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW
1.9 Factors affecting dissolution rate of SD
The dissolution profile of a poorly soluble drug can be enhanced through SD preparation. However, it is difficult to identify the primary factor behind such dissolution improvement, as several factors are usually at play. Based on literature search, the enhanced dissolution may be attributed to particle size reduction, drug porosity enhancement, wettability improvement, drug crystallinity reduction and/or processing condition.
17 1.9.1 Particle size reduction
During the preparation process, the size of the particles of an SD system is reduced. This phenomenon is especially clear when the drug is molecularly dispersed in the carrier, and in the case of glass and solid solutions. Particle size reduction leads to an improved dissolution rate due to the increased surface area and exposure to the dissolution media. The Kelvin equation provides a mathematical interpretation of the relationship between particle size and dissolution activity (Rouquerol et al., 2013), as follows:
𝒍𝒏 𝒂ₒ𝒂) 𝟐𝒚 ⊽
𝑹𝑻𝒓 (Equation 1.3)
; where = ratio of activity increase over a decrease in a large crystal r = crystal radius
y = surface area/energy of the crystal V = molar volume
T= temperture in Kelvin
This equation clarifies how a large surface area may be responsible for improvements in the dissolution performance of an SD system. However, a small particle size may also be equally important to prevent the recrystallization of an SD system.
1.9.2 Increased drug porosity
Particles in solid dispersion have been found to have high porosity (Kaur et al., 2016). The increased porosity of solid dispersion particles hastens
the drug release. Increase in porosity depends on carrier properties, i.e., linear polymers result in larger and more porous particles than that of reticular particles.
The capacity for a substance to crystallize in more than one crystalline form is polymorphism. It is possible that all crystals can crystallize in different forms or polymorphs. If the change from one polymorph to another is reversible, the process is called enantiotropy. If the system is monotropic, there is a transition point above the melting points of both polymorphs. The two polymorphs cannot be converted from one to another without undergoing a phase transition. Polymorphs can vary in melting point. Since the melting point of the solid is related to solubility, so polymorphs will have different solubilities. Generally, the difference in solubility between different polymorphs is only 2-3 folds due to relatively small differences in free energy.
1.9.4 Improved wettability
The carrier choice for an SD system can result in improved drug wettability.
For example, the dissolution performance of a piroxicam SD system was shown to be improved with the use of PVP as the carrier due to its hydrophilic nature, which causes a decrease in surface tension and increased wettability (Lust et al., 2015).
Improved wettability can indirectly lead to improved dissolution, namely, by preventing particle agglomeration and increasing the surface area of drug particles that are exposed to the dissolution media.
According to Song (2011), felodipine low dissolution rate was markedly improved when it was incorporated into an SD system using a hydrophilic polymer.
Another study showed that the polymers PEG 6000 and HPMC increased the dissolution performance of the API, as they created a favourable microenvironment.
Essentially, these polymers positioned themselves at high concentrations around the drug molecules.
Craig (2002) notes that in an SD system, a polymer forms a layer around the formulation, in which the drug dissolves upon contact with the dissolution media prior to being released (Marano et al., 2017). Jasmine et al (2015), demonstrated that the strong hydrophilic nature of PVP K90 improves water penetration to dissolve the hydrophobic molecule gliclazide more rapidly.
20 1.9.6 Decrease drug crystallinity
As mentioned earlier, the amorphous form of a drug generally exhibits higher solubility compared with the crystalline form, even within the same SD system. This phenomenon is because an amorphous state does not necessitate energy to breakdown strong bonds, as may be the case with a crystalline lattice. However, despite being more soluble, the amorphous drug form presents a major challenge, as it lacks the stability of the crystalline form.
1.9.7 Processing and storage conditions
The highest dissolution performance of an SD system can be obtained using an amorphous form of the components. Unfortunately, amorphous particles have a high tendency to undergo a transition into crystalline forms, which may be triggered by the temperature and humidity of their surroundings. This property renders the dissolution rate of an SD system dependent on the selection of the SD technique used and storage conditions. The cooling rate used in the Hot-Melt method, for instance, can influence the efficacy of the final SD product, because extended cooling may trigger rearrangements in amorphous particles and the creation of crystal nuclei.
Similarly, the solvent method is known to cause amorphous particles to undergo conversion into the crystalline form upon contact with the solvent. Moreover, compression and pulverisation during SD preparation may prompt particles to change into a more stable crystalline form.
21 1.10 Problem statement
The dissolution enhancement of SD systems has been demonstrated in many previous studies. However, some studies showed SD that did not significantly improve dissolution. Chan et al., 2016 revealed that SD formulation had little or no effect on the dissolution rates of Ketoprofen and naproxen. This implies that not all drugs produce improved dissolution performance after formulated as SD system.
The properties of drug/ carrier or factor that lead to the improved dissolution performance of SD system is still poorly understood. These have led to lack of commercial interest in the production of SD formulations, primarily because of multiple challenges pertaining to preparation, reproducibility, formulation, upscaling and stability of the final product.
SD techniques evolve with the discovery of new surfactants and emulsifying agents that can serve as carriers. Hence, researchers are encouraged to focus on investigating new carriers with valuable properties, as well as improving on existing carriers to enable their oral and topical usage. More carrier options may increase the chances of formulating better SD dosage forms in the future. Furthermore, efforts should be directed towards improving the stability of SD systems. The identification and assessment of new excipients and additives that may retard the conversion of amorphous forms into undesirable crystalline forms are key objectives.
Crystallization of an amorphous drug is a primary factor that can influence SD physical stability. Crystallization is a process that consists of the following two stages: nuclei formation and crystal growth (Markov et al., 2016). Both stages require mobile molecules that can form crystal nuclei and attach to one another to grow. Thus, molecular mobility is a key factor in crystallization and has a direct impact on the stability of SD systems. Several studies have shown that ASD
(amorphous solid dispersion) systems have a tendency to convert into the crystalline form and exhibit reduced dissolution performance with ageing.
Moisture and temperature are the most powerful factors that influence SD dissolution performance during storage. An early investigation of the stability of an indomethacin-PEG-6000 SD system showed a marked change in the dissolution profile and tablet colour of the system when it was stored at a temperature range of 25-41 ºC and an RH level of 71% due to the crystallization of indomethacin (Semjonov et al., 2017). The presence of active functional groups, such as carboxyl and hydroxyl moieties, in SD systems was recently shown to help reduce the risk of recrystallization upon storage (Christina et al., 2015). This phenomenon demonstrates the importance of polymer selection, as it may be a parameter that affects SD stability and the production of a completely miscible drug-carrier system.
Interestingly, stability issues may be overcome in certain cases by storing SD products at a temperature lower than their Tg values. This practice is believed to significantly lower molecular mobility and recrystallization tendencies.